This report includes work arising from the following clinical protocols: NCT00030147, NCT00060736, NCT00001231, NCT03689543 and NCT00001322. Our cross-sectional findings to date show that perimenopause-related depression (PMD) is accompanied by a decreased QOL, decreased social adjustment, increased negative life events and impaired role functioning comparable to depression occurring at other stages in a womans life. However, neither perimenopausal reproductive status alone nor the presence of hot-flushes had a significant negative impact on QOL measures. Nonetheless, it remains unclear whether the clinical characteristics we identified reflect pre-existing risk factors for PMD or the negative impact of a current depression. To clarify the relative relationship of these potential accompaniments to PMD we have conducted a high-density, prospective, longitudinal study during the past three decades. We expect to soon complete this study of healthy asymptomatic women who were followed with endocrine measures, symptom ratings, diagnostic and life events interviews before, during and after their transition through the menopause. . Approximately, ninety asymptomatic, premenopausal women, ages 41-55 years, were monitored longitudinally for an average of 5.2 years (range of 2 10 years) until 6-12 months after their final menses (FMP). Outcome measures included the Structured Clinical Interview for DSM-IV (SCID), as well as standardized measures of QOL and life events. Preliminary results in the first seventy-six women who have completed the study confirm the clustering of depressive episodes in proximity to the FMP. Twenty-nine episodes of major or minor (subsyndromal) depression occurred in twenty-three women, twenty-seven of these episodes occurred in the 2-years surrounding the FMP. The clustering of depressions during the late menopause transition, a time associated with declining levels of ovarian estradiol secretion, consistent with our clinic-based estradiol manipulation studies. During the four years prior to the FMP, compared to women who remained asymptomatic, women with PMD reported significantly lower life satisfaction but did not report significant differences in overall QOL, experience of personal loss, or negative life events. These data suggest that negative life events and decreased QOL/marital dissatisfaction do not uniformly precede the onset of PMD. Further, the relative absence of antecedent social or environmental events in PMD suggests a more specific role for hormonal events in the triggering of PMD. Preliminary findings from this longitudinal study also suggest that declining adrenal androgens (i.e., dehydroepiandrosterone) and progesterone-derived neurosteroids (i.e., allopregnanolone) contribute to this risk for PMD. The role of estradiol withdrawal in the onset of PMD was documented in our hormone manipulation studies in which we evaluated the effects of the acute withdrawal of estradiol therapy in asymptomatic postmenopausal women with and those without a past PMD. In this study, asymptomatic postmenopausal women who experienced a depression during the menopause transition and asymptomatic postmenopausal women with no past depression received a standard dose of estradiol (100 mcg per day). After three weeks all women were randomly assigned under double-blind (DB) conditions to either continue estradiol or switch to placebo (estradiol withdrawal). Estradiol withdrawal induced depressive symptoms in women with past PMD (n = 26), but not those without such a history (n = 30). Women with past PMD (but not those without past PMD) who were crossed over from estradiol to placebo (i.e., estradiol withdrawal) experienced a significant increase in depression symptom severity. Women with past PMD who were continued on estradiol and all control women remained asymptomatic. Importantly, women with past PMD and control women had similar hot-flush severity and plasma estradiol levels during placebo and, therefore, neither differences in hot-flushes (and the attendant sleep-disturbance) nor peripheral estradiol levels account for the differential response to estradiol withdrawal. In women with past PMD, the recurrence of depressive symptoms during blinded hormone withdrawal strongly suggests that normal changes in ovarian estradiol secretion triggers an abnormal behavioral state in these susceptible women. Clinically, these data also suggest that women with a history of PMD should be alert to the risk of recurrent depression when discontinuing hormone therapy. Additionally, we have completed a randomized clinical trial examining the effects on mood, cognitive performance and behavior in women with PMD. In this study, the therapeutic effects of estradiol and two novel compounds: the selective estrogen receptor (ER) modulator (SERM), raloxifene and a phytoestrogen (plant-derived estrogen-like compounds) under placebo-controlled conditions. A manuscript is in preparation in which we report a replication of our previous findings that estradiol therapy is effective in the treatment of PMD; however, neither raloxifene nor the phytoestrogen showed significant effects on depressive symptoms in PMD. The observed antidepressant effects of estradiol were independent of circulating estradiol levels and the severity of vasomotor symptoms (both similar to our previous findings with estradiol therapy in PMD. Findings from these studies conducted within the NIMH IRP as well as a recently published preventative trial of estradiol in PMD (performed by our collaborators at UNC, Chapel Hill) confirm the potential therapeutic value of estradiol in PMD. However, the long term safety profile of estrogen therapy as documented in the Womens Health Initiative prevents many women from employing hormonal therapy. Thus alternative forms of estradiol therapy with a more favorable long term safety profile are needed. To this end, we have commenced enrollment in our recently FDA-approved protocol, in which we explore whether the behaviorally-relevant estradiol withdrawal signal is mediated by ER alpha or beta (or both) by employing a selective ER beta agonist (LY500307). These data could identify a promising new class of therapeutic agents that are safer and more acceptable than estrogen and potentially lack the side effects or withdrawal syndromes associated with traditional psychotropics. Additionally, it is possible that the selectivity of these compounds for estrogen receptor alpha and beta may identify the mechanisms of efficacy of estradiol on specific target symptoms. Finally, in collaboration with David Goldmans laboratory at NIAAA, we investigate the effects of estradiol withdrawal on gene expression (whole transcriptome RNA-seq) in lymphoblastoid cell lines (LCLs) obtained from women with past PMD and controls who had the presence and absence, respectively, of estradiol withdrawal-induced depressive symptoms confirmed in the clinical study. These studies are performed before and after estradiol withdrawal in LCLs derived from women with past perimenopausal depression (PMD). We have completed RNA-sequencing, data analysis, and independent cohort validation in LCLs from women with PMD and matched controls. We have identified a role of E2-withdrawal on a cellular level in PMD. Our analysis demonstrated that the several genes involved with the inflammatory process and cardiovascular health are differentially expressed in women with PMD compared with control LCLs after estradiol withdrawal. These findings are relevant to the reported epidemiologic risks for heart disease (and death) in postmenopausal women with depression and will further inform our efforts to identify the role of declining adrenal androgen and neurosteroid secretion in the ontogeny of PMD given our preliminary findings from our longitudinal study (see above).